Photoreceptors function cooperatively with the retinal pigment epithelium (RPE) to optimize photon catch and generate signals that are transmitted to higher vision centers and perceived as a visual image. Disruption of the visual process in the retinal photoreceptors can result in blindness. Genetic defects in the retina cause substantial numbers of sight-impairing disorders by a multitude of mechanisms.
Among photoreceptor dystrophies, the X-linked forms of retinitis pigmentosa (XLRP) are one of the most common causes of severe vision loss. More than 25 years ago, the genetic loci were identified and discovery of the underlying gene defects followed. Human XLRP, caused by mutations in the Retinitis Pigmentosa GTPase Regulator (RPGR) gene, is a severe early onset retinal degenerative disease that accounts for the majority of XLRP. Mutations in the retinitis pigmentosa GTPase regulator (RPGR) gene account for >70% of the cases of XLRP, and exon ORF15, a mutational hot spot in RPGR, is mutated in 22-60% of patients. The disease is relentlessly progressive, and by the end of their fourth decade most patients are legally blind.
Until recently, progress has been slow in unraveling the molecular mechanisms that lead from mutation to PR degeneration, and in developing effective treatments for most forms of RP, including RPGR-XLRP. Disease-relevant animal models have been crucial in developing and validating new therapies. For RPGR-XLRP there are both mouse and canine models. In the dog, two naturally-occurring distinct microdeletions in ORF15 result in different disease phenotypes. X-linked progressive retinal atrophy 1 (XLPRA1; del 1028-1032) has a C-terminus truncation of 230 residues; the disease is juvenile, but post-developmental in onset, and progresses over several years. In contrast, the two-nucleotide deletion associated with XLPRA2 (del 1084-1085) causes a frameshift, and inclusion of 34 basic amino acids that changes the isoelectric point of the putative protein, and truncates the terminal 161 residues. The disease is early onset and rapidly progressive. Both models correspond to the disease spectrum of human XLRP, and, although differing in relative severity, they would be equivalent to human disease occurring within the first decade of life.
No successful treatment for XLRP is currently available to human patients suffering from this disease. What is needed is a treatment for RPGR-XLRP that is effective, safe and has long-term stability.